Background Lung adenocarcinoma (LAD) is a highly aggressive malignant tumor which threatens the health and life of the population. Long non-coding RNA X-inactive specific transcript (XIST) and mouse double minute clone 2 (MDM2) are connected with the tumorigenesis of LAD. Nevertheless, whether MDM2 is regulated by XIST has not previously been reported in LAD. Methods Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to detect the expression of XIST, microRNA-363-3p (miR-363-3p) and MDM2 in LAD tissues and cells. The proliferation, migration, invasion and apoptosis of LAD cells were determined by 3-(4, 5-dimethylthiazol-2-YI)-2, 5-diphenyltetrazolium bromide (MTT), transwell or flow cytometry assay, respectively. MDM2 protein level was detected using western blot analysis. Dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay and RNA pulldown assay were performed to determine the interaction among XIST, miR-363-3p and MDM2. A xenograft tumor model was constructed to validate the effect of XIST on LAD cells in vivo. Results We found that XIST and MDM2 were remarkably elevated while miR-363-3p was reduced in LAD tissues and cells. Both XIST and MDM2 downregulation restrained proliferation, migration and invasion, and facilitated apoptosis of LAD cells in vitro. Importantly, XIST bound to miR-363-3p to modulate MDM2 expression in LAD cells. Moreover, miR-363-3p knockdown or MDM2 elevation reversed the effects of XIST downregulation on the proliferation, migration, invasion and apoptosis of LAD cells. Furthermore, XIST knockdown constrained tumor growth on LAD cells in vivo. Conclusions XIST knockdown repressed proliferation, migration and invasion, and accelerated apoptosis of LAD cells by downregulating MDM2 expression via binding to miR-363-3p. Key points Significant findings of the study XIST and MDM2 were abnormally enhanced in LAD tissues and cells. Both downregulation of XIST and MDM2 repressed proliferation, migration and invasion, and boosted apoptosis of LAD cells in vitro. XIST bound to miR-363-3p to regulate MDM2 expression in LAD cells. Downregulation of XIST impeded tumor growth on LAD cells in vivo. What this study adds This study confirmed that XIST was a potential target for inhibiting the development of LAD, and affords a possible strategy for the treatment of LAD in the future.